The goal of this five-year career development program is to prepare Dr. Marc Levin for a career as an independent investigator dedicated to improving therapies for optic neuropathies. Neuromyelitis optica (NMO) is an autoimmune disease of the central nervous system associated with inflammatory demyelinating lesions in optic nerve and spinal cord. There is an urgent need for new treatments to prevent blindness in patients with NMO optic neuritis. Understanding the mechanisms of vision loss in NMO may identify new strategies for therapy. Most NMO patients are seropositive for immunoglobulin G (IgG) autoantibodies against the astrocyte water channel aquaporin-4 (AQP4). A passive-transfer NMO mouse model involving intracerebral injection of AQP4-IgG and human complement recapitulated the key pathological findings of NMO and confirmed the pathogenicity of AQP4-IgG, whose binding triggers complement- and cell-mediated astrocyte toxicity. As seen in human NMO lesions, secondary oligodendrocyte and neuronal damage coincides with activation of resident microglia and infiltration of circulating macrophages. However, optic nerve lesions are not easily studied in this model due to the low intrinsic complement activity of mouse. Rats possess a robust complement system similar to that in humans, which should provide a more physiologic background for evaluation of NMO optic neuritis. A new passive transfer model of NMO optic neuritis will be developed, potentially without the need to artificiall introduce complement, to determine the timing and mechanisms of neuro-inflammation in NMO optic neuritis (Specific Aim 1). In vivo rat models (or alternatively improved mouse or ex vivo models) will be used to test the hypothesis that microglial activation and macrophage recruitment by TNF-a signaling contributes greatly to axon demyelination and to irreversible retinal ganglion cell loss (Specific Aim 2). Finally, the therapeutic potential of a recently generated non-pathogenic recombinant monoclonal antibody that blocks binding of AQP4-IgG to AQP4 (the initiating event in NMO lesion formation) will be evaluated by optic nerve tissue pathology and using clinically relevant outcome measures of anterior visual pathway integrity, including optical coherence tomography, visual evoked potentials, and optokinetic responses (Specific Aim 3). The in vivo approaches detailed herein will provide important mechanistic information, and form the basis for ongoing studies to advance potential treatment of NMO and other optic neuropathies. Guidance and training will be provided by the mentor, Dr. Alan Verkman, a leading investigator in AQP biology who is devoted to better understanding NMO pathogenesis. A diverse team of co-mentors will offer complementary expertise in neuroimmunology and anterior visual pathway pathophysiology. This proposal will serve as an ideal platform for Dr. Levin to begin a career focused on basic mechanisms of neuro-ophthalmic disorders and their treatments.